Temporal patterns of circulating leptin levels in lean and obese adolescents: relationships to insulin, growth hormone, and free fatty acids rhythmicity.

Alterations in nutritional status, such as obesity, markedly influence insulin, leptin, GH secretion, and free fatty acid (FFA) levels. We measured every hour for 24 h circulating leptin, insulin, GH, and FFA levels in lean and obese adolescents to determine: 1) the impact of adolescent obesity on the diurnal changes in leptin concentrations; and 2) the temporal relationships between the diurnal patterns of circulating leptin levels and insulin, GH, and FFA levels. During puberty, we found that the 24-h profile of circulating plasma leptin levels follows a bimodal pattern with minimal concentrations occurring early in the afternoon and a nocturnal elevation starting after midnight and culminating early morning. The time course of the diurnal variation in leptin levels in the obese adolescents was not different from that in lean controls. Of note, however, in obese girls leptin 24-h excursion and leptin night to day ratio were lower than those found in lean girls. In obese adolescents, mean GH levels varied significantly less during the day and night than lean controls. During the day, there were distinct preprandial increases and postprandial decreases in FFA levels, whereas after midnight FFA levels rose in both lean and obese adolescents. A significant positive correlation was found between mean plasma insulin levels between 0800 h and 2000 h and peak in leptin in lean and obese girls and boys (r = 0.63, P: < 0.001). Peak leptin was inversely correlated with the area under the nocturnal GH levels in all groups (r = -0.31, P: < 0.0003), whereas it was positively correlated with the nocturnal peak in FFA levels (r = 0.45, P: < 0.004). In summary, we report in obese adolescent girls a blunted relative diurnal excursion in leptin levels. This abnormal rhythmicity may, in part, explain their leptin resistance state. The nocturnal rise in leptin was paralleled by a nocturnal rise in GH and FFA levels. Additional studies are needed to test the potential link between the adipose-derived peptide and GH axis in humans.

Oral glucose augments the counterregulatory hormone response during insulin-induced hypoglycemia in humans.

It has been suggested that the counterregulatory hormone (CRH) response to acute hypoglycemia is triggered via glucose sensors situated in either the hypothalamus or the portohepatic area. If the latter were critical during hypoglycemia, one would anticipate that ingestion of glucose, by raising glucose levels in the portal circulation, should attenuate CRH responses previously described in animal studies. To evaluate the effect of raising portal, but not peripheral, glucose levels during insulin-induced hypoglycemia, we performed hypoglycemic clamp studies in five healthy adult males on two occasions. On one occasion, subjects received oral glucose (OG) (25 g) during hypoglycemia; and on one occasion, noncarbohydrate-containing drink of equal volume, while maintaining plasma glucose at 55 +/- 2 mg/dL (3.08 mmol/L). As a result, there were no significant differences in systemic plasma glucose levels between the two hypoglycemic clamp studies, and basal CRH concentrations were also similar. As expected, there was a brisk rise in all CRH during the control (hypoglycemia+noncarbohydrate drink) study. In the experimental study, administration of OG (hypoglycemia+OG), to raise intraportal glucose levels during systemic hypoglycemia, did not attenuate CRH responses. Indeed, OG enhanced the rise in epinephrine, glucagon, and GH. Increases in cortisol and norepinephrine did not differ between the two studies. Therefore, our data suggest that increasing the level of glucose in the portal vein above that in the systemic circulation, during hypoglycemia, enhances (rather than suppresses) CRH responses. Thus, ingestion of glucose may reverse hypoglycemia directly by provision of substrate, as well as indirectly by stimulating counteregulatory mechanisms.

Augmentation of alimentary insulin secretion despite similar gastric inhibitory peptide (GIP) responses in juvenile obesity.

Insulin secretion rates are greater after oral glucose than after parenteral administration of an equivalent glucose load. This augmented beta-cell secretory response to an oral glucose load results from the release of mainly two gut hormones: gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1, which potentiate glucose-induced insulin secretion. Because of their insulinotropic action, their abnormal secretion may be involved in the pathogenesis of the hyperinsulinemia of childhood obesity. In this study, we used the hyperglycemic clamp with a small oral glucose load to assess the effect of childhood obesity on GIP response in seven prepubertal lean and 11 prepubertal obese children and in 14 lean adolescents and 10 obese adolescents. Plasma glucose was acutely raised to 11 mM by infusing i.v. glucose and kept at this concentration for 180 min. Each subject ingested oral glucose (30 g) at 120 min, and the glucose infusion was adjusted to maintain the plasma glucose plateau. Basal insulin and C-peptide concentrations and insulin secretion rates (calculated by the deconvolution method) were significantly greater in obese children compared with lean children (p < 0.001). Similarly, during the first 120 min of the clamp, insulin secretion rates were higher in obese than lean children. After oral glucose, plasma insulin, C-peptide, and insulin secretion rates further increased in all four groups. This incretin effect was 2-fold greater in obese versus lean adolescents (p < 0.001). Circulating plasma GIP concentrations were similar at baseline in all four groups and remained unchanged during the first 120 min of the clamp. After oral glucose, plasma GIP concentrations rose sharply in all groups (p < 0.002). Of note, the rise in GIP was similar in both lean and obese children. In conclusion, under conditions of stable hyperglycemia, the ingestion of a small amount of glucose elicited equivalent GIP responses in both lean and obese children. However, despite similar GIP responses, insulin secretion was markedly augmented in obese adolescents. Thus, in juvenile obesity, excessive alimentary beta-cell stimulation may be independent of the increased release of GIP.

Familial medullary thyroid carcinoma: presymptomatic diagnosis and management in children.

Two kindreds with familial medullary thyroid carcinoma (MTC) are described in which affected family members had variable clinical and pathologic manifestations. Genetic testing in 2 children from one kindred revealed a mutation in exon 10, codon 618 (TGC to AGC) in the extracellular cysteine-rich region of the RET gene. In this kindred an 11-year-old had microscopic evidence of MTC; however, a 17-year-old had no evidence of pathology on thyroidectomy. In a second kindred a rare mutation in exon 14, codon 804 (GTG to TTG) of the intracellular tyrosine kinase region of the RET gene was detected. In this kindred MTC has occurred in the 4th to 5th decades of life, with a clinical spectrum in mutation-positive family members ranging from no disease and C-cell hyperplasia to carcinoma with lymph node metastasis; a 7-year-old with the mutation and a normal response to provocative testing was also identified. Management recommendations in children from families with clearly defined familial MTC may be individualized to reflect emerging genotype-phenotype correlations.

Changes in free insulin-like growth factor-1 and leptin concentrations during acute metabolic decompensation in insulin withdrawn patients with type 1 diabetes.

UNLABELLED: To determine the effect of acute insulin withdrawal and its subsequent replacement on components of the insulin-like growth factor (IGF)-1 binding protein system and on circulating leptin levels in patients with type 1 diabetes. Seventeen patients (age 31 yr +/-10) with type 1 diabetes treated with continuous subcutaneous insulin infusion (HbA1c 7.6% +/-1.0) were studied. The protocol consisted of two phases: acute insulin withdrawal of up to 8 h followed by a further 2-h period of insulin replacement. For the first phase the basal insulin infusion was stopped (at 0300 h), and for the second a single dose of either regular human or insulin lispro was given subcutaneously (0.2 U/kg). Plasma insulin, glucose, growth hormone, glucagon, IGF-1, free IGF-1, IGFBP-1, -2, -3 and leptin were measured. RESULTS: After interruption of the basal insulin infusion, plasma free insulin levels fell from 60+/-12.0 pmol/L to 10.8+/-4.2 pmol/L, and plasma glucose rose from 5.6+/-0.4 mmol/L to 14.8+/-1.2 mmol/L (P< 0.01). During insulin withdrawal, IGFBP-1 increased by more than 6-fold (from 32+/-8 to 205+/-17 ng/mL, P<0.001), IGFBP-3 increased significantly (from 2631+/-118 to 3053+/-101 ng/mL, P<0.001), and total IGF-1 levels declined modestly (from 226+/-33 to 182+/-26 ng/mL, P<0.001). In contrast, free IGF-1 concentrations (0.72+/-0.22 ng/mL at baseline) were markedly suppressed during insulin withdrawal to values below the detection limit of the assay (0.08 ng/mL) in 15 of the 17 patients (P<0.001). Circulating plasma leptin declined markedly in females from 20+/-3 ng/mL to 11+/-2 ng/mL (P<0.0001) and in males from 10+/-2 ng/mL to 7+/-2 ng/mL (P<0.02). Within 2 h of insulin replacement, the changes in circulating concentrations of IGFBP-1 and IGFBP-3 were partially reversed, and free IGF-1 levels rebounded to 0.54+/-0.22 ng/mL (P<0.1 vs. insulin withdrawal). Growth hormone, glucagon, and IGFBP-2 levels did not change significantly throughout the study. Despite the rapid restoration of plasma insulin and substrate levels, circulating leptin levels continued to fall in the 2-h period after insulin replacement in both females and males. The marked reduction in circulating free IGF-1 after insulin withdrawal and its increase after insulin administration suggest that acute changes in IGFBP concentrations induced by insulin are important regulators of IGF-1 bioavailability in patients with type 1 diabetes. In both males and females, the rapid induction of severe insulin deficiency is associated with a consistent fall in plasma leptin levels.

The metabolic syndrome and insulin-like growth factor I regulation in adolescent obesity.

Although low GH levels are commonly seen in obese adults and children, the effects of obesity on the insulin-like growth factor (IGF)/IGF-binding protein (IGFBP) system have not been established. As GH and IGF-I normally increase during adolescence, we investigated the effects of obesity on circulating total and free IGF-I levels and IGFBP-1, -2, and -3 in 19 obese adolescents [14 +/- 1 yr old; body mass index (BMI), 34 +/- 3], 20 lean adolescents (14 +/- 1 yr old; BMI, 23 +/- 0.5), and 10 lean adults (22 +/- 0.7 yr; BMI, 22 +/- 0.7). Fasting plasma insulin levels were significantly greater in obese adolescents than in either lean group, whereas circulating IGFBP-1 levels were suppressed in an inverse relationship to basal insulin (r = -0.49; P < 0.01). Low IGFBP-1 levels were associated with normal to increased free IGF-I levels in obese adolescents, even though total IGF-I values were lower than those in lean adolescents. Basal GH and IGFBP-3 levels were also lower in obese vs. lean adolescents. Basal IGFBP-1 levels were markedly reduced in obese adolescents (14 +/- 3 ng/mL) vs. those in adolescents and adults. No further suppression of IGFBP-1 levels was observed in the obese group during a two-step 8 and 40 mU/m2 insulin clamp. In contrast, IGFBP-1 levels were promptly lowered in lean adults. Basal IGFBP-2 levels were significantly lower in both groups of adolescents vs. lean adults (P < 0.05), and IGFBP-2 levels did not change during euglycemic hyperinsulinemia. These data suggest that the compensatory hyperinsulinemia that characterizes adolescent obesity chronically suppresses levels of IGFBP-1, and low IGFBP-1 concentrations may serve to increase the bioavailability of free IGF-I, which may, in turn, contribute to lower circulating GH, total IGF-I, and IGFBP-3 concentrations.

Decreased insulin sensitivity and compensatory hyperinsulinemia after hormone treatment in children with short stature.

To assess the effects of GH treatment on carbohydrate and protein metabolism, we studied eight patients with short stature before and after the commencement of GH treatment. The hyperglycemic clamp procedure was employed to produce a hyperglycemic stimulus of 50 mg/dL above fasting levels for 120 min. These patients were then treated with 0.3 mg/kg. week GH for 6 months, after which they were restudied. Patients were compared to eight healthy control children matched for age, sex, and Tanner stage. Fasting plasma glucose did not change significantly, but fasting plasma insulin levels were higher after GH therapy (P < 0.005). Despite identical glucose increments during the glucose clamp procedure, both first, and second phase insulin responses were markedly greater after instituting GH treatment. Even in the face of higher mean plasma insulin levels after GH treatment, the rate of insulin-stimulated glucose metabolism did not differ during the last 60 min of both studies. Hence, the rate of insulin-stimulated glucose metabolism/mean plasma insulin ratio (an index of insulin sensitivity) was sharply reduced after GH treatment (P < 0.01). During the clamp, the fall in circulating branched chain amino acid levels was significantly greater after GH therapy (P < 0.02). We conclude that glucose-stimulated insulin responses are increased in short children treated with GH and that such hyperinsulinemic responses compensate for reductions in insulin sensitivity. The compensatory hyperinsulinemic responses induced by GH therapy may serve a beneficial role by augmenting insulin's anabolic effects on protein metabolism.